In a groundbreaking study set to reshape our understanding of immune defense, researchers have unveiled a novel molecular role for myeloperoxidase (MPO) in the formation and effector function of neutrophil extracellular traps (NETs). Contrary to its well-established function as a catalyst for antimicrobial hypohalous acid production, MPO now emerges as a pivotal chromatin-transforming agent that orchestrates the intricate reorganization of nuclear DNA during NETosis. This discovery not only adds a remarkable new dimension to the biology of MPO but also proposes a paradigm shift in how chromatin dynamics can be repurposed by immune cells to combat infection and mediate inflammatory responses.
At the heart of this conceptual advance lies the observation that MPO operates in two distinct structural states—monomeric and dimeric forms—each conferring unique functional consequences upon chromatin architecture. Researchers delineated that the dimeric form of MPO directly facilitates chromatin decondensation, a critical step in dismantling the tightly packed nucleosomal arrays that compose nuclear DNA. This decondensation enables the extrusion of chromatin fibers into the extracellular space, forming the characteristic NET structures that neutrophils deploy to trap and neutralize invading pathogens.
Strikingly, the mechanism through which dimeric MPO induces chromatin unfolding defies the canonical paradigms of chromatin remodeling. While typical chromatin remodelers rely on enzymatic activity fueled by ATP hydrolysis, MPO drives nucleosome disassembly without any energy expenditure, leveraging a unique molecular interaction with the nucleosome acidic patch. Structural analyses revealed that MPO’s binding mode mimics other nucleosome interactors but diverges by instigating a steric clash at nucleosomal DNA crossover sites. This clash destabilizes the DNA ends, promoting unwrapping and ultimately ejecting DNA from histone cores to disassemble the nucleosome.
Notably, the inherent dynamic nature of nucleosomes under physiological conditions provides a fertile ground for MPO’s disruptive influence. The transient exposure of DNA ends in untreated nucleosomes, which typically does not culminate in eviction, becomes exacerbated upon dimeric MPO binding. This effectively shifts the equilibrium from a stable chromatin state toward a decondensed configuration, underscoring how MPO acts as a molecular wedge facilitating nucleosome destabilization. These subtle yet decisive interactions highlight an unprecedented modality of chromatin transformation that operates independent of enzymatic chromatin remodeling machinery.
Conversely, monomeric MPO adopts a contrasting role by occupying the nucleosome’s acidic patch without inducing DNA displacement. Instead of promoting nucleosome eviction, monomeric MPO serves as a protective agent, shielding nucleosomes from the disruptive effects of their dimeric counterparts. This stable binding mode explains why monomeric MPO decorates extracellular NET structures, potentially amplifying their antimicrobial capacity through continued hypohalous acid production. The spatial detachment of MPO’s catalytic site from its DNA interaction surface enables this dual functionality, neatly segregating enzymatic and structural roles within the same protein complex.
The researchers propose a nuanced model of MPO action during NETosis whereby both oligomeric forms co-exist and compete for binding sites on chromatin. Initially, MPO binds chromatin weakly and non-specifically via DNA backbone interactions, before the acidic patch engagement locks either monomeric or dimeric MPO tightly onto nucleosomes. This competition determines the fate of chromatin domains, with some regions undergoing decondensation and disassembly driven by dimeric MPO, while others are preserved in compacted nucleosome–MPO complexes stabilized by the monomeric form. Such heterogeneity likely underpins the complex architecture of NETs and the multifaceted functional roles they play outside the cell.
Expanding beyond mechanistic details, this study challenges the classical definition of MPO deficiency, which has focused primarily on reduced catalytic activity. The newfound recognition of MPO’s chromatin-binding and nucleosome evicting capabilities invites a re-evaluation of this clinical phenotype. Functional impairments in chromatin interaction and destabilization could contribute to disease manifestations linked to defective NET formation, including infections, autoimmune disorders, and oncogenic processes. This research thus opens novel diagnostic and therapeutic avenues targeting the non-catalytic functions of MPO.
Importantly, MPO’s ability to irreversibly remodel chromatin into a biologically repurposed state diverges from any conventional chromatin remodeling complexes. Its action defines a new class of chromatin-transforming factors whose primary function is not gene regulation but rather structural and functional conversion of chromatin for immune defense purposes. This redefined chromatin state is characterized by a loss of replicative and transcriptional capacity, reflecting a fundamental alteration in chromatin identity, which empowers neutrophils to deploy NETs efficiently without maintaining genetic information integrity.
The evolutionary implications of such a repurposing mechanism are profound, suggesting that eukaryotic chromatin can serve as a versatile substrate adapted for diverse roles beyond its canonical functions. This paradigm may extend beyond neutrophils to other cell types and contexts, potentially involving similar or yet unidentified proteins that transform extracellular chromatin originating from necrotic or stressed cells into functionally adapted structures. The concept of chromatin versatility therefore acquires new significance, linking immunity, inflammation, and tissue homeostasis.
From a therapeutic perspective, deciphering the molecular basis of MPO-chromatin interaction offers strategic targets for modulating NET formation and activity. Inhibitors designed to prevent MPO binding to the nucleosome acidic patch could selectively disrupt chromatin decondensation during NETosis, thereby attenuating NET-driven pathological inflammation without compromising MPO’s enzymatic antimicrobial function. Such specificity holds promise for treating diseases exacerbated by excessive NET production, including sepsis, thrombosis, and autoimmune conditions.
The integration of high-resolution microscopy, cryogenic electron microscopy, and biochemical assays in this study provides an unprecedented structural framework to understand MPO’s dual modus operandi. The correlation between structural observations—ordered versus disordered nucleosomal DNA ends—and biochemical nucleosome stability highlights the dynamic interplay of molecular constraints imposed by MPO binding. This comprehensive approach underscores the power of multidisciplinary strategies to unravel complex biological phenomena at molecular resolution.
Overall, this illuminating research reveals myeloperoxidase as a versatile chromatin transformer at the crossroads of innate immunity and chromatin biology. By bridging structural biochemistry with immune cell function, it opens exciting new avenues for exploring how chromatin can be harnessed and adapted in diverse biological contexts. As we expand our knowledge of chromatin’s plasticity, MPO may serve as a prototype for an entirely new class of chromatin-altering proteins, redefining the cellular and extracellular roles of DNA and histone complexes in health and disease.
Subject of Research: The role of myeloperoxidase (MPO) in chromatin transformation during neutrophil extracellular trap (NET) formation and function.
Article Title: Myeloperoxidase transforms chromatin into neutrophil extracellular traps.
Article References:
Burn, G.L., Raisch, T., Tacke, S. et al. Myeloperoxidase transforms chromatin into neutrophil extracellular traps. Nature (2025). https://doi.org/10.1038/s41586-025-09523-9
Image Credits: AI Generated
Tags: antimicrobial mechanisms of neutrophilschromatin dynamics in immune responsechromatin remodeling mechanisms in immunologydimeric MPO and chromatin decondensationimmune cell chromatin transformationmolecular biology of myeloperoxidaseMPO and chromatin reorganizationmyeloperoxidase role in immune defenseNET structures and pathogen neutralizationNETosis and immune functionneutrophil extracellular traps formationnovel roles of MPO in inflammation
